Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours.

INTRODUCTION: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. OBJECTIVES: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. METHODS: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC)0-48, AUC0-inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC0-48 and AUC0-inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. CONCLUSIONS: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS. GOV IDENTIFIER: NCT03147378, date of registration: May 10 2017.

Incidence Changes of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma and Effects on Survival in the Netherlands Cancer Institute, 1980-2009.

AIM: Human papillomavirus (HPV) is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence. The present study aimed to determine the changing incidence of HPV in patients with OPSCC in the period 1980-2009 and its influence on survival. PATIENTS AND METHODS: We randomly sampled 158 patients from a cohort of 828 patients with OPSCC stratified by decade (1980-1989, 1990-1999, 2000-2009). Formalin-fixed paraffin-embedded material was tested for HPV DNA by SPF-10 polymerase chain reaction (PCR) and immunohistochemically stained for p16 and p53. RESULTS: DNA from 146 patients was suitable for HPV detection. HPV DNA was detected in 13/47 (28%), 18/47 (38%), and 20/52 (38%) patients in the cohorts of 1980-1989, 1990-1999, and 2000-2009, respectively (p-value for trend=0.269). Lack of further increase during the most recent decade is inconsistent with the rising incidence and higher prevalence reported in other Western countries. Patients with HPV-positive OPSCC had a better survival in spite of higher tumor stage.

Oral and oropharyngeal squamous cell carcinoma in young patients: the Netherlands Cancer Institute experience.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) mainly affects patients between the fifth and seventh decade of life but is increasingly seen in young patients (<40 years old). Controversy exists in the literature regarding outcomes for younger patients with HNSCC. METHODS: A retrospective cohort analysis was performed comparing survival of 54 early-onset (<40 years) and 1708 older patients with oral and oropharyngeal squamous cell carcinomas (SCC) treated at The Netherlands Cancer Institute between 1977 and 2008. Survival analysis was performed using univariable and multivariable weighted Cox proportional hazards regression. The primary endpoint for the survival analysis was disease-specific survival (DSS). RESULTS: There was no difference in DSS between patients who were 40 years or younger and those older than 40 years (p = .878), although young patients had significantly better overall survival (OS). CONCLUSION: In this series, patients younger than 40 years with oral and oropharyngeal SCC showed no significant difference in DSS compared with patients older than 40 years, even when adjusted for tobacco and alcohol consumption.